Family, twin and adoption study demonstrated evidence for importance of genetic factors in bipolar disorder (Gershon et al 1990). The mode of inheritance does not follow the Mendelian rules and multiple genes (Risch and Botsein 1996) with likely complex gene-gene (Berrettini 1999) and gene-environment interaction are likely to be involved.
Different linkage studies have investigated the short arm of chromosome 11 in bipolar families since the first evidence for linkage in an Old Order Amish kindred (Egeland et al 1987). This finding however was not replicated in the reanalysis of the families after the disease occurred in some individuals that were unaffected in the primary analysis (Kelsoe et al 1989). Further linkage studies of 11p in several data sets of bipolar families have failed to show consistent results (Detera-Wadleigh et al 1987; Nothen et al 1990; Byerley et al 1992; Sidenberg et al 1994; Smyth et al 1996; Smith et al 1997; Malafosse et al 1997).
Interestingly, the short arm of chromosome 11 on p15.5 harbors two dopamine system genes, i.e. the dopamine D4 receptor (DRD4) and the tyrosine hydroxylase (TH) genes, which are both of interest for bipolar disorder. Preliminary evidence for the involvement of dopamine pathways in bipolar disorder aroused from animal studies, more recently evidence from pharmacological and behavioural studies in humans continue to support a dopaminergic role in the etiology of bipolar disorder (Willner 1995).
The gene for the dopamine D4 receptor is highly polymorphic, containing a functional variable number of tandem repeat (VNTR) in the third exon, the region of the gene that encodes for the intracellular loop of the receptor (Van Tol et al 1992; Asghari et al 1995). The polymorphism consists of 2 to 11 imperfect tandem repeat of 48 bp, coding for 16 amino acids. Thirty-five variations of the sequence within the 48 bp repeat, that generate 56 haplotypes, have been described (Lichter et al, 1993; Ding et al 2002). Most of these haplotypes are extremely rare with a frequency of less than 1%. Each of the repeat alleles has one variant that is much more common than the others, for example the most common variant of the 4 repeat allele has a frequency of 95% (Ding et al 2002). In vitro studies have found different pharmacological properties for the D4 receptors coded by the 2, 4 7 and 10 repeat alleles (Asghari et al 1995, Jovanovic et al 1999). Tyrosine hydroxylase is the rate-limiting enzyme in the synthesis of catecholamines that converts tyrosine to DOPA. Its gene contains a microsatellite in the Intron I constituted by a tetranucleotide repeat of (TCAT)n motif (HUMTH01) that can be repeated five to 10 times (Polymeropulos et al 1991), the 10 repeat alleles can be present in two different sequence variants (Puers a et al 1993). A recent in vitro study suggests that the microsatellite HUMTH01 may be implicated in the regulation of the gene expression (Meloni et al 1998).
There remains a need to identify genetic polymorphisms that may be useful in determining a person's susceptibility to bipolar disorders.